The objective of the proposed research is to elucidate the role of Rab proteins in 1-synuclein toxicity. Alpha-synuclein (1Syn) is a principal component of Lewy bodies found pathologically in Parkinson disease (PD) and related disorders, such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Abnormal folding, aggregation, and deposition of 1Syn are believed to be central to development of neuronal dysfunction and degeneration. Recent data in yeast indicate that over-expression of 1Sy interferes with intracellular trafficking and results in abnormal vesicle accumulation, clustering, and toxicity. Rab proteins are members of the Ras super-family of small GTP-binding proteins and have critical functions in intracellular trafficking, membrane transport, and even neurotransmitter release. Over-expression of Rab proteins in several PD models, including yeast, worms, and flies, as well as rodent primary neurons, rescues 1Syn toxicity. Moreover, Rab proteins show increased binding to 1Syn in several neurodegenerative disorders, including DLB, MSA, and possibly also PD. Oligomeric forms of mutant 1Syn likewise appear to have increased Rab binding. Our own preliminary data confirm Rab proteins'protective role, and show that they also reduce the amount of oligomeric forms of 1Syn present in cell models of 1Syn toxicity. Together, these findings support the hypothesis that accumulation of 1Syn interferes with normal Rab function, leading to toxicity via disruption of intracellular trafficking. Alternatively, specific Rab proteins may normally protect against formation and accumulation of toxic 1Syn species, but are overwhelmed by overexpression in model systems and pathological conditions, such as PD. Enhancing Rab function may thus provide a new therapeutic opportunity for PD and related neurodegenerative disorders. The proposed experiments will therefore discern the mechanisms whereby Rab overexpression confers protection against 1Syn. My long-term goal is to develop a career aimed at understanding and ultimately finding novel therapies for PD and related neurodegenerative disorders through basic and translational research. The proposed research and career development plan, under the supervision of Dr. Bradley Hyman, will help achieve my immediate goals to obtain up-to-date molecular and genetic skills and to learn state-of-the-art imaging techniques to complement my strong neuroanatomical background. Additional expertise in viral manipulation and CNS gene delivery methods from Drs. Xandra Breakefield and Miguel Esteves will also forward my goal of eventually becoming a gene therapy expert and translating my work into potential patient therapies. Developing these research skills, along with my continued clinical training and experience are critical to becoming a successful, independent clinician-scientist committed to translational neuroscience. PUBLIC HEALTH RELEVANCE: The results of the proposed research are particularly relevant and critical to understanding the role of 1- synuclein in Parkinson disease and related neurodegenerative disorders. The proposed studies will test the hypothesis that 1-synuclein interferes with Rab protein function and intracellular trafficking, leading to neuronal dysfunction and toxicity. Furthermore, over-expression of Rabs may ameliorate this toxicity.